chr1-16021917-T-C

Variant names:

• chr1-16021917-T-C
• rs945425
• ENST00000375692.5:c.-82T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000375692.5(CLCNKA):​c.-82T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,618 control chromosomes in the GnomAD database, including 38,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.70 (37935 hom., cov: 33)
  • Exomes 𝑓: 0.75 (153 hom.)
• Consequence: CLCNKA ENST00000375692.5 splice_region
• Scores: Splicing: ADA: 0.00007013
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 17 publications found

Genes affected

CLCNKA (HGNC:2026): (chloride voltage-gated channel Ka) This gene is a member of the CLC family of voltage-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar to CLCNKB, which is located 10 kb downstream from this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CLCNKA Gene-Disease associations (from GenCC):

• Bartter disease type 4B

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
• Bartter syndrome type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375692.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKA	NM_004070.4	MANE Select	c.-154T>C		upstream_gene	N/A	NP_004061.3
	CLCNKA	NM_001042704.2		c.-154T>C		upstream_gene	N/A	NP_001036169.1	P51800-3
	CLCNKA	NM_001257139.2		c.-154T>C		upstream_gene	N/A	NP_001244068.1	P51800-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKA	ENST00000375692.5	TSL:1	c.-82T>C		splice_region	Exon 1 of 21	ENSP00000364844.1	P51800-3
	CLCNKA	ENST00000375692.5	TSL:1	c.-82T>C		5_prime_UTR	Exon 1 of 21	ENSP00000364844.1	P51800-3
	CLCNKA	ENST00000861484.1		c.-82T>C		splice_region	Exon 1 of 21	ENSP00000531543.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106851 AN: 151972 Hom.: 37913 Cov.: 33

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.975

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.714

GnomAD4 exome AF: 0.752 AC: 397 AN: 528 Hom.: 153 Cov.: 0 AF XY: 0.751 AC XY: 314 AN XY: 418

African (AFR) AF: 0.889 AC: 16 AN: 18

American (AMR) AF: 0.500 AC: 2 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.950 AC: 19 AN: 20

South Asian (SAS) AF: 0.750 AC: 3 AN: 4

European-Finnish (FIN) AF: 0.917 AC: 11 AN: 12

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 0.741 AC: 323 AN: 436

Other (OTH) AF: 0.633 AC: 19 AN: 30

GnomAD4 genome AF: 0.703 AC: 106923 AN: 152090 Hom.: 37935 Cov.: 33 AF XY: 0.702 AC XY: 52214 AN XY: 74340

African (AFR) AF: 0.739 AC: 30662 AN: 41500

American (AMR) AF: 0.643 AC: 9830 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2102 AN: 3466

East Asian (EAS) AF: 0.974 AC: 5035 AN: 5168

South Asian (SAS) AF: 0.640 AC: 3081 AN: 4816

European-Finnish (FIN) AF: 0.729 AC: 7699 AN: 10566

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46290 AN: 67980

Other (OTH) AF: 0.713 AC: 1500 AN: 2104

Alfa AF: 0.684 Hom.: 133958

Bravo AF: 0.698

Asia WGS AF: 0.792 AC: 2752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.79
DANN	Benign	0.41
PhyloP100		-1.5
PromoterAI		-0.034	Neutral
Mutation Taster		=252/48	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.0020

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs945425; hg19: chr1-16348412;